tbuckley/cabot-search huggingface dataset:
Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements
Authors: Gennaro D’Amico, Alexander Zipprich, Càndid Villanueva, Juan Antonio Sordà, Rosa Maria Morillas, Matteo Garcovich, Montserrat García Retortillo, Javier Martinez, Paul Calès, Mario D’Amico, Matthias Dollinger, Marta García-Guix, Esteban Gonzalez Ballerga, Emmanuel Tsochatzis, Isabel Cirera, Agustìn Albillos, Guillaume Roquin, Linda Pasta, Alan Colomo, Jorge Daruich, Nuria Canete, Jérôme Boursier, Marcello Dallio, Antonio Gasbarrini, Angelo Iacobellis, Giulia Gobbo, Manuela Merli, Alessandro Federico, Gianluca Svegliati Baroni, Pietro Pozzoni, Luigi Addario, Luchino Chessa, Lorenzo Ridola, Guadalupe Garcia-Tsao
Journal: Hepatology (2023)

Background and Aims: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. Approach and Results: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and &lt;1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23–1.71) ( p &lt;0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. Conclusions: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.
Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC
Authors: Anna-Lena Scherr, Luisa Nader, Kaiyu Xu, Christin Elssner, Dirk A. Ridder, Federico Nichetti, Manuel Mastel, Sarah Fritzsche, Eblina Kelmendi, Nathalie Schmitt, Paula Hoffmeister-Wittmann, Sofia M. E. Weiler, Felix Korell, Thomas Albrecht, Maximilian Schwab, Hanna Isele, Annika Kessler, Jennifer Hüllein, Agnieszka Seretny, Liangtao Ye, Toni Urbanik, Stefan Welte, Anne-Laure Leblond, Christoph E. Heilig, Mohammad Rahbari, Adnan Ali, Suchira Gallage, Bénédicte Lenoir, Nina Wilhelm, Ulrike Gärtner, Simon J. Ogrodnik, Christoph Springfeld, Darjus Tschaharganeh, Stefan Fröhling, Thomas Longerich, Henning Schulze-Bergkamen, Dirk Jäger, Lydia Brandl, Peter Schirmacher, Beate K. Straub, Achim Weber, Enrico N. De Toni, Benjamin Goeppert, Mathias Heikenwalder, Rene Jackstadt, Stephanie Roessler, Kai Breuhahn, Bruno C. Köhler
Journal: Hepatology (2023)

HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established.
Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer
Authors: Jessica E. Hawley, Aleksandar Z. Obradovic, Matthew C. Dallos, Emerson A. Lim, Karie Runcie, Casey R. Ager, James McKiernan, Christopher B. Anderson, Guarionex J. Decastro, Joshua Weintraub, Renu Virk, Israel Lowy, Jianhua Hu, Matthew G. Chaimowitz, Xinzheng V. Guo, Ya Zhang, Michael C. Haffner, Jeremy Worley, Mark N. Stein, Andrea Califano, Charles G. Drake
Journal: Cancer Cell (2023)

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.
Surgical methods of total thyroidectomy for differentiated thyroid cancer: A systematic review and Bayesian network meta-analysis
Authors: Yuquan Yuan, Bin Pan, Enjie Tang, Hongbiao Mo, Junping Zhu, Ziying Yi, Dengwei Lu, Tingjie Yin, Yiceng Sun, Supeng Yin, Zeyu Yang, Fan Zhang
Journal: International Journal of Surgery (2023)

Background: Emerging remote-access surgical methods are utilized to treat differentiated thyroid cancer. The study aimed to compare the surgical integrity, safety, efficacy, and postoperative experience of patients among common surgical methods. Methods: PubMed, Medline, Cochrane Library, Web of Science, and EMBASE databases were searched from their inception until March 2023. Pairwise meta-analysis and Bayesian network meta-analysis were performed. The surface under the cumulative ranking curve (SUCRA) was used to illuminate the probability that each method would be the best for each outcome. Results: Thirty-two studies comprising 7042 patients were included. Robotic bilateral axillo-breast approach (RBABA) and robotic gasless transaxillary approach (RGAA) retrieved fewer lymph nodes (LNs) than open thyroidectomy (OT). RBABA showed a significantly lower permanent recurrent laryngeal nerve (RLN) palsy rate than OT. According to SUCRA values, endoscopic transoral approach (EOA) ranked the highest in retrieved LNs (0.84), the proportion of stimulated serum thyroglobulin &lt; 1.0 ng/mL (0.77), and the pain score (0.77). Endoscopic bilateral areola approach (EBAA) ranked the highest in the transient RLN palsy rate (0.72). Endoscopic gasless transaxillary approach (EGAA) ranked the highest in the transient hypoparathyroidism rate (0.78). RBABA ranked the highest in the rate of permanent RLN palsy (0.94) and hypoparathyroidism (0.77). OT ranked the highest in operative time (0.92). Conclusions: Each surgical method of total thyroidectomy has benefits and limitations. EOA performed the best in maintaining surgical integrality and reducing the pain score, while taking a long operative time. Generally, RBABA showed the best advantage in protecting parathyroid glands and RLN but with the longest operative time. OT had the best advantage in operative time. Therefore, OT and EOA are ideal methods for patients with a higher risk of central LN metastasis. RBABA and EOA may not be suitable for elderly patients or those with high anesthesia risk.
Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary <i>PIK3CA</i> Mutations
Authors: Andreas Varkaris, Ferran Fece de la Cruz, Elizabeth E. Martin, Bryanna L. Norden, Nicholas Chevalier, Allison M. Kehlmann, Ignaty Leshchiner, Haley Barnes, Sara Ehnstrom, Anastasia-Maria Stavridi, Xin Yuan, Janice S. Kim, Haley Ellis, Alkistis Papatheodoridi, Hakan Gunaydin, Brian P. Danysh, Laxmi Parida, Ioannis Sanidas, Yongli Ji, Kayao Lau, Gerburg M. Wulf, Aditya Bardia, Laura M. Spring, Steven J. Isakoff, Jochen K. Lennerz, Kathryn Del Vecchio, Levi Pierce, Ermira Pazolli, Gad Getz, Ryan B. Corcoran, Dejan Juric
Journal: Cancer Discovery (2023)

PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers. In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 240 . This article is featured in Selected Articles from This Issue, p. 201.
Risk stratification of papillary thyroid cancers using multidimensional machine learning
Authors: Yuanhui Li, Fan Wu, Weigang Ge, Yu Zhang, Yifan Hu, Lingqian Zhao, Wanglong Gou, Jingjing Shi, Yeqin Ni, Lu Li, Wenxin Fu, Xiangfeng Lin, Yunxian Yu, Zhijiang Han, Chuanghua Chen, Rujun Xu, Shirong Zhang, Li Zhou, Gang Pan, You Peng, Linlin Mao, Tianhan Zhou, Jusheng Zheng, Haitao Zheng, Yaoting Sun, Tiannan Guo, Dingcun Luo
Journal: International Journal of Surgery (2023)

Background: Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies with different risk levels. However, preoperative risk assessment of PTC is still a challenge in the worldwide. Here, we first report a Preoperative Risk Assessment Classifier for PTC (PRAC-PTC) by multidimensional features including clinical indicators, immune indices, genetic feature, and proteomics. Materials and methods: The 558 patients collected from June 2013 to November 2020 were allocated to three groups: discovery set (274 patients, 274 FFPE), retrospective test set (166 patients, 166 FFPE) and prospective test set (118 patients, 118 FNA). Proteomic profiling was conducted by formalin-fixed paraffin-embedded (FFPE) and fine-needle aspiration (FNA) tissues from the patients. Preoperative clinical information and blood immunological indices were collected. The BRAF V600E mutation were detected by the amplification refractory mutation system (ARMS). Results: We developed a machine learning model of 17 variables based on multidimensional features of 274 PTC patients from a retrospective cohort. The PRAC-PTC achieved areas under the curve (AUC) of 0.925 in the discovery set and validated externally by blinded analyses in a retrospective cohort of 166 PTC patients (0.787 AUC) and a prospective cohort of 118 PTC patients (0.799 AUC) from two independent clinical centres. Meanwhile, the preoperative predictive risk effectiveness of clinicians was improved with the assistance of PRAC-PTC, and the accuracies reached at 84.4% (95% CI 82.9-84.4) and 83.5% (95% CI 82.2-84.2) in the retrospective and prospective test sets, respectively. Conclusion: This study demonstrated that the PRAC-PTC that integrating clinical data, gene mutation information, immune indices, high-throughput proteomics and machine learning technology in multi-centre retrospective and prospective clinical cohorts can effectively stratify the preoperative risk of PTC and may decrease unnecessary surgery or overtreatment.
Translational Aspects of Epithelioid Sarcoma: Current Consensus
Authors: Thomas G.P. Grünewald, Sophie Postel-Vinay, Robert T. Nakayama, Noah E. Berlow, Andrea Bolzicco, Vincenzo Cerullo, Josephine K. Dermawan, Anna Maria Frezza, Antoine Italiano, Jia Xiang Jin, Francois Le Loarer, Javier Martin-Broto, Andrew Pecora, Antonio Perez-Martinez, Yuen Bun Tam, Franck Tirode, Annalisa Trama, Sandro Pasquali, Mariagrazia Vescia, Lukas Wortmann, Michael Wortmann, Akihiko Yoshida, Kim Webb, Paul H. Huang, Charles Keller, Cristina R. Antonescu
Journal: Clinical Cancer Research (2023)

Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ∼50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene, SMARCB1-a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.
Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
Authors: Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A. Boezio, Artemisa Bulku, Lucian DiPietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P. Hamilton, Katherine Harris, Michael Holliday, Tamieka L. Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R. LaRochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M. Mader, Brenton G. Mar, Iain Martin, Thomas H. McLean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M. Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R. Williams, Hongtao Zeng, Hanmo Zhang, W. Patrick Walters, Beni B. Wolf, David E. Shaw, Donald A. Bergstrom, James Watters, James S. Fraser, Pascal D. Fortin, D. Randal Kipp
Journal: Cancer Discovery (2023)

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.
High pathological grade might discourage early invasive breast cancer patients who have a pathologic complete response to neoadjuvant systemic therapy from eliminating breast surgery
Authors: Chaofan Li, Yusheng Wang, Mengjie Liu, Jingkun Qu, Shuqun Zhang
Journal: International Journal of Surgery (2023)

Li, Chaofan MD; Wang, Yusheng MD; Liu, Mengjie MD; Qu, Jingkun; Zhang, Shuqun Author Information
Inflammatory stress response after transanal vs laparoscopic total mesorectal excision: a cohort study based on the TaLaR trial
Authors: Mian Chen, Fujin Ye, Pinzhu Huang, Zhenxing Liang, Huashan Liu, Xiaobin Zheng, Wenxin Li, Shuangling Luo, Liang Kang, Liang Huang
Journal: International Journal of Surgery (2023)

Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer; however, it is not clear whether taTME causes a more severe inflammatory stress response than laparoscopic total mesorectal excision (laTME). Therefore, the authors conducted this study to address this question, with the secondary objective of analyzing the predictive effect of inflammatory indexes on postoperative infective complications between laTME and taTME.
A comment on ‘Ulnar shortening osteotomy vs. wafer resection for ulnar impaction syndrome: A systematic review and meta-analysis’
Authors: Lei Zhang, Weili Fu
Journal: International Journal of Surgery (2023)

Sports Medicine Center, Department of Orthopedic Surgery/ Orthopedic Research Institute, West China Hospital, Sichuan University All data generated or analyzed during this study are included in this article. The data are available from the corresponding author upon reasonable request. A commentary on "Ulnar shortening osteotomy vs. wafer resection for ulnar impaction syndrome: A systematic review and meta-analysis" Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author. Address: Sichuan University West China Hospital, Chengdu, China. E-mail address: [email protected] (W. FU). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0/
An optimized post-surgery follow-up strategy for patients with esophageal cancer: a cohort study
Authors: Zihang Mai, Jiaxin Xie, Changsen Leng, Xiuying Xie, Jing Wen, Hong Yang, Qianwen Liu, Jianhua Fu
Journal: International Journal of Surgery (2023)

Background: After radical surgery, patients with esophageal cancer should undergo long-term surveillance of disease relapse. However, the optimal follow-up strategy remains to be explored. Method: A total of 4688 patients were recruited. Recursive partition analysis was applied to develop recurrence risk stratification for patients. The follow-up strategies of each stratification were developed based on monthly recurrence probability and validated by bootstrap validation and an external dataset. Markov decision-analytic model was constructed to evaluate the cost-effectiveness of the follow-up strategies. Results: Patients were stratified into four groups according to four pathological features. We applied random survival forest to calculate the monthly recurrence probability of each group. Based on the temporal distribution of recurrences, we further established surveillance strategies for four groups. The strategies were validated as optimal protocols by bootstrap resampling and another dataset. Markov decision-analytic analysis indicated that our recommended strategies outperformed the mainstream protocols from guidelines and were most cost-effective. Using less than 12 visits across the first 5 years on average, our follow-up strategies were more efficient than the NCCN recommended strategies (14 visits average). Our results also supported the computerized tomography from the neck to the upper abdomen as routine examination and PETCT of distant metastasis for some groups with high risks. Conclusion: Our study provided data-driven evidence of personalized and economic follow-up strategies for EC patients and shed light on follow-up optimization for other cancer types.
Early innate role for CD8αα+ cells in tuberculosis
Authors: Daniel L. Barber
Journal: The Journal of Experimental Medicine (2023)

Cell types that mediate early control of Mycobacterium tuberculosis (Mtb) infection are not well understood. Winchell and Nyquist et al. (https://doi.org/10.1084/jem.20230707) show that CD8αα+ lymphocytes have a major role in the innate suppression of Mtb growth in the lungs of macaques.